Androgen effectors

Abstract

The invention discloses novel endocrine treatment phytochemicals which affect androgenic status. The method for treatment of 5-alpha-reductase responsive diseases using four novel 5-alpha-reductase inhibitor compounds; leucoanthocyanidin, glabrene, glabridin, and alpha-terpineol is disclosed. Glabridin does not interfere with normal testosterone to androgen receptor binding.

The invention claimed is: 
     
       1. A novel androgen effector method for treating diseases responsive to 5-alpha reductase inhibition and non-antiandrogenicity, comprising administering to a human or mammal subject in need thereof a therapeutic composition or formulation comprising a therapeutically effective amount of 5-alpha reductase inhibitor glabridin as an active principle, via an effective dosage form in a pharmaceutically acceptable vehicle, wherein 5-alpha reductase is inhibited and levels of dihydrotestosterone in the subject are reduced, and wherein the overall level of testosterone to androgen receptor signaling in the subject is not reduced in the presence of glabridin;
 wherein the therapy may or may not exert an estrogenic effect; 
 said nonestrogenic 5-alpha reductase inhibiting therapeutically effective amount of glabridin being that which achieves a serum concentration of about the IC50 of 29 ug/ml for glabridin, but less than 10-4 M (32 ug/ml) and more than 10-7 M (32 ng/ml) glabridin based on pure reference standard of glabridin; 
 said estrogenic 5-alpha reductase inhibiting therapeutically effective amount of glabridin being that which achieves a serum concentration above 10-4 M (32 ug/ml) glabridin based on pure reference standard of glabridin; 
 said therapeutic composition of formulation comprises 0.0001 wt%-20 wt% glabridin plus one or more excipients. 
 
     
     
       2. A method for treating diseases responsive to 5-alpha reductase inhibition and non-antiandrogenicity comprising the steps of administering 0.0001 wt%-20 wt% glabridin as the active principle in a therapeutic composition or formulation to a human or mammal subject in need thereof, wherein the improvement comprises that 5-alpha reductase is inhibited while the overall level of testosterone to androgen receptor signaling in the subject is not reduced in the presence of glabridin and glabridin when dosed to achieve a serum concentration of between 10-7 M and 10-4 M is estrogenic. 
     
     
       3. A novel androgen effector method for treating diseases responsive to 5-alpha reductase inhibition without reducing testosterone to androgen receptor agonism, consisting essentially of administering to a human or mammal subject in need thereof a therapeutic composition or formulation of 0.0001 wt%-20 wt% glabridin delivering a therapeutically effective amount of 5-alpha reductase inhibitor glabridin as the active principle, and furthermore optionally containing at least one further active agent selected from the list consisting of alpha-linolenic acid, alpha terpineol, Angelica Tenuissima, arachidonic acid, artocarpin, beta-sitosterol, biochanin-A, coconut medium chain fatty acids, daidzein, dutasteride, epicatechin, epigallocatechin, finasteride, flutamide, gamma linolenic acid (GLA), genistein, glabrene, leucoanthocyanidin, licochalcone A, linoleic acid, myristoleic acid, oleic acid, palm fruit kernel, palmitic acid, palmitoleic acid, papverine, Perilla sikokiana, PDE5 inhibitors, phentolamine, phenoxybenzamine, phytosterlos, prostaglandin E2, pumpkin seed extract, protogracillin, Pygium africanum, S. Flavescens, secoisolariciresinol, Serenoa Repens, sildenafil, solasodine, stearic acid, testosterone, testosterone receptor agonists, unsaturated fatty acids, vasoacive intestinal polypeptide or VIP, and other 5-alpha reductase inhibitor agents via an effective dosage form in a pharmaceutically acceptable vehicle, wherein 5-alpha reductase is inhibited and levels of dihydrotestosterone in the subject are reduced. 
     
     
       4. A novel androgen effector method for treating diseases responsive to 5-alpha reductase inhibition, majority non-antiandrogenicity, and to estrogenicity, comprising administering to a human or mammal subject in need thereof a therapeutic composition or formulation comprising a therapeutically effective amount of the 5-alpha reductase inhibitor glabrene or leucoanthocyandin as an active principle, via an effective dosage form in a pharmaceutically acceptable vehicle;
 wherein said treatment thereby maintains majority binding activity for agonism of testosterone to androgen receptor in the presence of glabrene, is estrogenic, and inhibits 5-alpha reductase, and levels of dihydrotestosterone in the subject are reduced; 
 said effective amount of active principle is that which achieves a therapeutic serum level of about the IC50 of 5 ug/ml for glabrene and 30 ug/ml for leucoanthocyanidin. 
 
     
     
       5. A novel androgen effector method for treating diseases responsive to 5-alpha reductase inhibition and majority non-antiandrogenicity and to estrogenicity, consisting essentially of administering to a human or mammal subject in need thereof a therapeutic composition or formulation consisting essentially of a therapeutically effective amount of the 5-alpha reductase inhibitor glabrene or leucoanthocyanidin as an active principle, via an effective dosage form in a pharmaceutically acceptable vehicle, and furthermore optionally containing at least one further active agent selected from the list consisting of alpha-linolenic acid, alpha terpineol, Angelica Tenuissima, arachidonic acid, artocarpin, beta-sitosterol biochanin-A, coconut medium chain fatty acids, daidzein, dutasteride, epicatechin, epigallocatechin, finasteride, flutamide, gamma linoleic acid (GLA), genistein, glabrene, leucoanthocyanidin, licochalcone A, linoleic acid, myristoleic acid, oleic acid, palm fruit kernel, palmitic acid, palmitoleic acid, papverine, Perilla sikokiana, PDE5 inhibitors, phentolamine, phenoxybenzamine, phytosterols, prostaglandin E 2 , pumpkin seed extract, protogracillin, Pygium africanum, S. Flavescens, secoisolariciresinol, Serenoa Repens, sildenafil, solasodine, stearic acid, testosterone, testosterone receptor agonists, unsaturated fatty acids, vasoactive intestinal polypeptide or VIP, and other 5-alpha reductase inhibitor agents, wherein said treatment thereby maintains majority binding activity for agonism of testosterone to androgen receptor in the presence of leucoanthocyanidin or glabrene, is estrogenic, and inhibits 5-alpha reductase and levels of dihydrotestosterone in the subject are reduced. 
     
     
       6. The method of  claim 3  or  5  whereby the composition contains a therapeutically effective amount of at least one further agent selected from the list consisting of alpha-linolenic acid, alpha terpineol, Angelica Tenuissima, arachidonic acid, artocarpin, beta-sitosterol, biochanin-A, coconut medium chain fatty acids, daidzein, dutasteride, epicatechin, epigallocatechin, finasteride, flutamide, gamma linolenic acid (GLA), genistein, glabrene, leucoanthocyanidin, licochalcone A, linoleic acid, myristoleic acid, oleic acid, palm fruit kernel, palmitic acid, palmitoleic acid, papaverine, Perilla sikokiana, PDE5 inhibitors, phentolamine, phenoxybenzamine, phytosterols, prostaglandin E2, pumpkin seed extract, protogracillian, Pygium africanum, S. Flavescens, secoisolariciresinol, Serenoa Repens, sildenafil, solasodine, stearic acid, testosterone, testosterone receptor agonists, unsaturated fatty acids, vasoactive intestinal polypeptide or VIP, and other 5-alpha reductase inhibitor agents. 
     
     
       7. The method of  claim 5  wherein the 5-alpha reductase inhibitor is leucoanthocyanidin, and said leucoanthocyanidin is administered in a dose of 10-20 mg/day.